Currently, many efforts are done, and many resources are used to research on the area of cancer immunotherapy. Important existing evidences indicate a central role of T lymphocytes in cancer effective immune responses (Oliver R T, Nouri A M. T; Cancer Surv 1992; 13:173-204). To such purpose, treatments with allogenic cells alone, with adjuvants, or in combination with some cytokines have been used.
On the other hand, it is known that dendritic cells (DC) are antigen presenting cells that may initiate a T cell response, due to their extraordinary ability to stimulate naïve T lymphocytes (Schuler G, Steinman R M. J. Exp. Med. 1997; 186:1183-7, and Banchereau J, Steinman R M. Nature 1998; 392:245-52).
Several authors have shown in mouse models, and in humans that DC incorporate apoptotic cells, and thus the antigens for the generation of Class I HLA complexes/peptides are presented, allowing the induction of cytotoxic T lymphocytes (Albert M L, Pearce S F, Francisco L M, Sauter B, Roy P, Silverstein R L, Bhardwaj N. J Exp Med. 1998, 188: 1359-1368; Chen Z, Moyana T, Saxena A, Warrington R, Jia Z, Xiang J. Int J. Cancer. 2001, 93: 539-548 and Shaif-Muthana M, McIntyre C, Sisley K, Rennie I, Murray A. Cancer Res. 2000, 60: 6441-6447). For this process it is fundamental that the apoptotic cells induce maturity of the dendritic cells (DC), however, many authors have informed that human apoptotic cells do not mature DC, or induce loss of maturity of such DC (Pietra G, Mortarini R, Parmiani G, Anichini A. Cancer Res 2001, 61: 8218-8226; Labarriere N, Bretaudeau L, Gervois N, Bodinier M, Bougras G, Diez E, Lang F, Gregoire M, Jotereau F. Int J Cancer 2002, 101: 280-286 and Demaria S, Santori F R, Ng B, Liebes L, Formenti S C, Vukmanovic S. J Leukoc Biol. 2005, 77: 361-368).
U.S. Pat. No. 6,187,306 by Pardoll et al. discloses a method of treating and protecting against melanoma, which comprises the use of at least one or more allogenic cell lines expressing melanoma immunodominant antigens, wherein the cell line has been modified in such a way that it expresses cytokines, and administering such transformed line to a patient carrying melanoma, or at risk of getting the disease. Although the importance of the cell line or the cell lines used, which expresses most of the immunodominant antigens, a new cell line or a combination of cell lines expressing most of such antigens have not been disclosed. The invention comprises essentially transformed cell lines expressing cytokines such as GM-CSF.
U.S. Pat. No. 5,882,654, and U.S. Pat. No. 5,840,317 disclose irradiated melanoma cell lines used as allogenic vaccines. The disclosed treatment reaches levels of NED patients below 50% (16/37), and shows an effective humoral-type anti-tumor activity.
US patent 2006/0034811 by Wallack et al. discloses vaccines comprising antigen presenting cells charged with lysed or ruptured tumor cells including cytosol and membranes. Tumor cells may be cells from the patient, cell lines, or cells infected with the recombinant vaccinia virus codifying IL-2. US patent 2006/0140983 by Palucka et al. discloses a composition inducing immunity in cancer patients which comprises the isolation and purification of antigen presenting cells primed for exposition with one or more heat-shock proteins, and dead tumor cells. Antigen presenting cells are dendritic cells, and tumor cells may be syngenic or allogenic cells, for example cell lines. This document discloses the need of incorporating heat-shock proteins by rupture through heating of tumor cells. The shown assays do not necessarily disclose that the composition have immunity-inducing activity in melanoma patients.
U.S. Pat. No. 6,602,709 by Albert et al., discloses the use of apoptotic cells to present antigens to dendritic cells for T cell induction. The method is useful to induce antigen-specific cytotoxic T lymphocyte helper cells. Dendritic cells are primed by apoptotic cells or fragments thereof, and are capable of processing and present processed antigens, and induce the activity of cytotoxic T lymphocytes, which may be used as therapeutic vaccines.